Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by resting tremor, rigidity and bradykinesia. These clinical features are thought to arise from reduced dopaminergic input to the striatum, which is caused by the degeneration of dopaminergic neurons in the substantia nigra. The occurrence of Parkingson's disease is largely sporadic, but clinical syndromes resembling sporadic Parkingson's disease can also be caused by mutations in the alpha-synuclein, parkin, DJ-1 and PINK1 genes. Elucidation of the pathogenic mechanisms underlying the selective dopaminergic degeneration in familial Parkinsonism will likely provide important clues to the pathogenic mechanisms responsible for idiopathic Parkingson's disease. The recessive inheritance mode of the mutations and the existence of large exonic deletions in the parkin, DJ-1 and PINK1 genes indicate that loss of function of a single gene product can lead to clinical manifestations of Parkinsonian and selective dopaminergic degeneration. We take advantage of the identification of these genes to study the mechanisms by which loss-of-function mutations in these genes result in manifestations of Parkinsonian features through the generation of mutant mice. Our previous generation and analysis of parkin-/- mice have shown nigrostriatal deficits and mitochondria! dysfunction in the absence of loss of dopaminergic neurons, suggesting that these functional deficits likely precede neurodegeneration, and that mitochondrial dysfunction may be causal in PD pathogenesis. More recently, we found that young DJ-1-/- mice exhibit hypoactivities in the open field and alterations in evoked dopamine release and dopamine-regulated neuronal activities. In this proposal, we hypothesize that loss-of-function mutations in the PINK1 gene alter the normal physiology of dopaminergic neurons in the substantia nigra, and that inactivation of all three recessive Parkinsonian genes accelerates dopaminergic dysfunction and degeneration, leading to progressive loss of dopaminergic neurons in mice. To test these hypotheses, we propose the following two Specific Aims. First, we will generate and analyze PINK 1-/- mice for disruption of normal dopaminergic neurotransmission, loss of dopaminergic neurons, mitochondrial dysfunction and motor impairments. Second, since parkin-/- mice fail to develop dopaminergic degeneration in the lifespan of mice, we will investigate whether the presence of all three pathogenic mutations in triple mutant mice (parkin-/-; DJ-1-/-; P1NK1-/-) accelerates the degeneration of dopaminergic neurons. Our long-term goal is to develop a genetic mouse model that recapitulates all central features of Parkingson's disease and to characterize the molecular pathways responsible for PD pathogenesis.